Uric acid is generated by catabolizing purine, which is formed by decomposition of nucleic acid and adenosine triphosphate (ATP) which is an energy source of the living body, and then by oxidizing the metabolized purine, xanthine, by xanthineoxidase or xanthinedehydrogenase. In case of humans, uric acid (dissociation constant pKa=5.75) is a final metabolite of purine, and is present in the body as a free uric acid or salt.
Uric acid is usually excreted in urine, and hyperuricaemia is caused when uric acid production exceeds its excretion and uric acid in blood is increased. When an excess of uric acid level in blood over upper limit (about 7 mg/dL) of solubility continues for a long period, a crystal of a urate (usually sodium salt) is precipitated.
Urate crystal is deposited on cartilaginous tissues or joints to form a precipitate, and thus leading to gouty node. Whereby, acute gouty arthritis is caused and evolved to chronic gouty arthritis.
When the crystal of the urate is precipitated in urine, renal damage (gouty kidney) such as interstitial nephritis, urinary stone and the like are created. After calming down of stroke of acute gouty arthritis, pharmacotherapy is performed together with the life style improvement support so as to correct hyperuricaemia.
It is important to correct hyperuricaemia and to appropriately manage a uric acid value so as to prevent acute gouty arthritism, gouty kidney, urinary stone and the like.
It is considered that hyperuricaemia is complicated by lifestyle-related diseases such as obesity, hyperlipemia, abnormal glucose tolerance and hypertension at a high rate (see Non-Patent Literature 1 (pp 7-9)). An increase in serum urate concentration exhibits a positive relationship with a death rate due to cardiovascular diseases. Since high serum urate concentration increases death due to cardiovascular diseases, it is suggested that an increase in serum uric acid level is singly and significantly involved in a risk of death due to cardiovascular diseases, (see Non-Patent Literature 2).
It is also suggested that the serum urate concentration is a strong risk factor of myocardial infarction and cerebral haemorrhage (see Non-Patent Literature 3). It has been reported until now that hyperuricaemia is associated with obesity, hyperlipemia, dyslipidemia, abnormal glucose tolerance, diabetes, metabolic syndrome, renal disease (for example, renal insufficiency, urine protein, end stage kidney disease (ESRD), etc.), cardiovascular diseases (for example, hypertension, coronary artery disease, carotid artery disease, endothelial dysfunction, arteriosclerosis, cardiac hypertrophy, cerebrovascular disease, etc.) or a risk factor of these diseases (see Non-Patent Literatures 2 to 11). It has also been reported that the concentration of uric acid in the cerebrospinant increases in vascular dementia (see Non-Patent Literature 12).
Under these circumstances, it is suggested that decrease in blood urate level can delay the proceeding of renal disease, and also can reduce a risk of cardiovascular disease (see Non-Patent Literatures 5, 8, 13 and 14), and it is reported that the treatment should also be applied to asymptomatic hyperuricaemia (see Non-Patent Literature 14).
Accordingly, it is considered that a decrease in blood urate level in the above-mentioned diseases is effective for the treatment or prevention of these diseases, and is also important from the viewpoint of preventing the recurrence of cardiovascular accident and maintaining a renal function.
The main factor of an increase in blood urate level include overproduction and underexcretion of uric acid. It is considered that a method for suppression of the production of uric acid or acceleration of excretion of uric acid is effective as a method for decreasing a blood urate level. It is known that a drug (uric acid production inhibitor) having a mechanism of action of the former includes allopurinol, while a drug (uricosuric drug) having a mechanism of action of the latter includes benzbromarone, probenecid, JP-A-2006-176505 (Patent Literature 1) or the like.
Japanese guidelines for the management of hyperuricemia and gout describes that, in case of a treatment of hyperuricaemia, a uricosuric drug is applied for patients with underexcretion of uric acid and a uric acid production inhibitor is applied against patients with overproduction of uric acid, respectively, as a general Hide (see Non-Patent Literature 1 (pp. 31-32)).
It is said in Japan that patients with underexcretion of uric acid account for about 60% of hyperuricaemia patients and mix type patients with both underexcretion and overproduction of uric acid account for about 25% of hyperuricaemia patients (Non-Patent Literature 15). It is also reported that underexcretion of uric acid is observed in about 85% of gout patients, and even in patients with overproduction of uric acid, an average of uric acid clearance is significantly lower than that of a healthy person, and underexcretion of uric acid as a common phenomenon in all gout patients is suggested (Non-Patent Literature 16).
Accordingly, treatment for patients with underexcretion of uric acid is considered to be important in hyperuricaemia (particularly gout) and significance of the existence of a uricosuric drug is remarkably great.
Among main uricosuric drugs, probenecid is scarcely used since it has a weak action, and gastrointestinal disturbance and an interaction with other drugs are recognized, while serious liver damage is reported in benzbromarone which has a strong uricosuric action and is popularly used as a uricosuric drug in Japan (see Non-Patent Literature 17).
Benzbromarone or an analog thereof exhibits mitochondria toxicity, for example, inhibition of enzyme complex activity of a respiratory chain of mitochondria, uncoupling action, inhibition of respiration, inhibition of fatty acid β oxidation, reduction in mitochondria membrane potential, apoptosis, production of reactive oxygen species and the like, and it is suggested that mitochondria toxicity is involved in the onset of liver damage (see Non-Patent Literatures 18 and 19). An active metabolite of benzbromarone, 6-hydroxy benzbromarone also exhibits toxicity against mitochondria.
Furthermore, benzbromarone has an action of inhibiting cytochrome P450 (CYP) which is a drug metabolizing enzyme and reveals particularly strong inhibition against CYP2C9, and it is suggested to cause a pharmacokinetic drug interaction (see Non-Patent Literatures 20 and 21).
JP-A-2006-176505 (Patent Literature 1) describes a nitrogen-containing fused ring compound, which has an inhibitory action on URAT1 as a kind of urate transporters and also has a structure analogous to that of the compounds of the present invention. However, the compound does not have a sufficient effect and a practicable novel uricosuric drug has not been developed yet.
There has recently been obtained a finding that an uricosuric action depends on the concentration of a drug having the same action in urine, that is, a uricosuric drug exhibits drug effectiveness by being excreted in urine (see Patent Literature 2, Non-Patent Literatures 22 and 23).
Accordingly, more potent, effective uricosuric drug which is excreted in urine in larger quantities is expected. However, the above existing uricosuric drug shows drastically low concentration in urine, and it cannot be said that satisfactory activity is obtained.
With respect to excretion of the drug in urine, the case where the administered drug is excreted as an unchanged compound as it is, and the case where the drug is converted into an active metabolite and then excreted can be estimated. In the latter case, there is a risk that an individual difference in production amount of the active metabolite may increase. In order to obtain stable drug effectiveness and safety, a drug to be excreted as an unchanged compound is more desirable.
[So, it is desired to develop a pharmaceutical which exhibits a high concentration of an unchanged compound in urine, and also has a remarkable uricosuric action and high safety as compared with an existing uricosuric drug.